Stress, Neurodevelppment and the Emergence of Addictive Behaviors in Adolescence (Project 6 of 14): Adolescence is a critical period for the emergence of addictive behaviors that not only place adolescents at immediate risk for morbidity and for accidents, suicide, and violent behavior (the leading causes of death in this age group), but also contribute to lifelong increases in major medical morbidity and early mortality. Though childhood stress is known to be a major risk factor for the development of addictive behaviors in adolescence, there is a paucity of study of the mechanisms by which stress leads to the emergence of addictive behaviors in teens. Our pilot data suggest that childhood stress alters development of ventral prefrontal cortex (VPFC) control over amygdala and ventral striatum responses to emotional stimuli, resulting in excessive drive towards hedonic stimuli, impulsivity and addictive behaviors. This project establishes a new collaboration between co-Pis Drs. Blumberg and Mayes to bring together their respective expertise in multimodality magnetic resonance imaging (MRI) study of adolescent brain development and modeling the influences of psychosocial factors on the development of adaptive emotional and social behaviors in children and adolescents. This will provide unique opportunities to study how psychosocial stressors in childhood alter cortico-limbic development to contribute to the emergence of addictive behaviors in adolescence. This study team will include Drs. Kalmar, Mazure, Nicholls, Nolen-Hoeksema, Ryan, Wang and other consortium collaborators to integrate perspectives including Adolescent Medicine, Neurobiology, Neuroimaging, Neuropsychology, Pediatrics, Psychiatry, Psychology and Women's Health. Dr. Mayes has followed a unique cohort prospectively since birth, now entering adolescence, carefully characterized with biannual assessments for biopsychosocial factors. We plan to study 70 adolescents from this cohort, ages 14-17 years (50% girls): 35 with a history of childhood maltreatment and 35 without a history of maltreatment. Dr. Blumberg's group will perform functional MRI and diffusion tensor imaging to examine regional brain response to emotional stimuli within cortico-limbic circuitry, the functional connectivity between components within this circuitry, as well as the integrity of the structural white matter connections in the circuitry. Consortium core (Projects 13,14) measures of stress, biological factors and addictive behaviors will provide rich opportunities for study, including interactions between stress and genetic variations associated with biogenic amine regulation of the amygdala-ventral striatum-VPFC neural system (as in 2,3,7,8) in influencing the emergence of addictive behaviors. Collaboration with Drs. Potenza and Neumeister (7,8) will provide opportunities to examine similarities and differences between adolescents and adults, and novel treatments tested (5,9,10) will provide the basis for future innovative prevention and early intervention strategies.